This invention relates to the general field of controlling angiogenesis--i.e., preventing or treating undesired angiogenesis.
Various diseases are angiogenesis-dependent, in that they are related to the process by which new capillary blood vessels are formed. Uncontrolled and rampant capillary growth can cause extensive tissue damage, e.g. in diabetic retinopathy where neovascularization in the retina may lead to blindness and in rheumatoid arthritis where new vessels in the joint may destroy articular cartilage. Moreover, the progressive growth of tumors generally depends upon continuous induction of angiogenesis.
Folkman, "Tumor Angiogenesis" in Advances in Cancer Research, Vol. 43, pp. 175-203 (Klein and Weinhouse, Eds.) generally reviews efforts to find angiogenesis inhibitors which might be used therapeutically, in an effort to control angiogenesis-dependent diseases. Specifically, mixtures of cortisone (or hydrocortisone) and heparin (or heparin fragments) inhibit angiogenesis, as measured by regression of growing capillaries in chick embryo, cessation of tumor-induced capillary growth in rabbit cornea, and regression of some tumors in mice. Folkman et al. Science 221:719 (1983). This anti-angiogenic activity is not dependent upon the anticoagulant activity of heparin, nor upon the glucocorticoid or mineralocortocoid activity of steroids. Crum and Folkman, J. Cell Biol. 99:158a, Abstr. #581 (1984); and Crum et al. Science 230:1375 (1985). The same effect is observed with several natural and synthetic steroids, and they appear to act by inducing basement membrane breakdown, endothelial cell rounding, and capillary retraction. Ingber et al. Endocrinology 119:1768 (1986).
Controlled alterations of extracellular matrix metabolism have been suggested as control points in capillary development. Folkman and Ingber, Annal. Surg. 206:374 (1987); Ingber et al., In Vitro Cell Devel. Biol. 23:387 (1987).
Substitution of certain proline analogs in place of proline in collagen interferes with protein folding, and aberrant triple helix formation results in impaired secretion of interstitial collagens and acceleration of intracellular collagen degradation. Jimenez and Yankrowski, J. Biol. Chem. 253:1420 (1978); and Berg et al. Proc. Nat'l. Acad. Sci. USA 77:4746 (1980). Incorrectly folded basement membrane collagen may be secreted, but it is not deposited within organized extracellular matrices, Madri and Stenn, Am. J. Pathol. 106:180 (1982); Maragoudakis et al. Biochem. Biophys. Acta. 538:139 (1978); Wicha et al. Exp. Cell. Res. 124:181 (1979); Wicha et al. Dev. Biol. 80:253 (1980). Migration of endothelial cells can be inhibited by using proline to interfere with collagen deposition in vitro. Madri et al., cited above. Cells treated with proline analogs exhibit inhibition of collagen deposition into extracellular matrix, although accumulation of non-collagenous protein usually is not significantly affected. Uitto et al. Arch. Biochem. Biophys. 173:187 (1976); Blocking basement membrane collagen deposition inhibits growth of 7,12 -dimethylbenzanthracene induced rat mammary tumors. Wicha et al. Cancer Letters 12:9 (1981).
Proline analogs and .alpha.,.alpha.-dipyridyl (DPY) interfere with morphogenesis of a variety of tissues including cornea (Coulombre and Coulombre, Dev. Biol. 28:183 (1972)), cartilage (Aydelotte and Kochmer, Dev. Biol. 28:191 (1972)), thyroid gland (Harris et al., Science 208:177 (1980)); salivary gland and lung (Spooner and Faubion, Dev. Biol. 77:84 (1980)), and mammary gland (Wicha et al., Dev. Biol. 80:253 (1980)). Vembu et al., Exp. Cell Res. 124:247 (1979); Kidwell et al., "Growth Arrest of Mammary Tumors By Proline Analogs" in Progress In Cancer Research and Therapy (Bresciani et al., eds) Vol. 31, p. 129, Raven Press, N.Y., N.Y., 1984.